A Heart Artificial: Building the Foundation for the Development and Maintenance of In Vitro Tissue Mimetic Cardiovascular Models

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Abstract

Given the prevalence of cardiovascular disorders and the distinct lack of significant repair mechanisms within cardiovascular systems, effective therapy for long-term treatment of cardiovascular degeneration remains a significant challenge. Further, the fundamental importance of such systems to all mammalian life begs the development of realistic component structures for in vitro assessment.
Significant effort was expended to create in vitro models which mimicked a subset of structure and function of coordinate native components within cardiovascular systems. Towards this end, we developed a 3D-Artificial Heart Muscle (AHM) model utilizing fibrin gel and neonatal cardiac myocytes. We extracted functional metrics in order to probe the optimal protocol for generation of the tissue model. Building on the outcome of this experiment, we applied the optimal 3D-AHM model to a decellularized adult rat heart in order to re-append function to a complex acellular scaffold. The resultant bioartifical heart (BAH) model was assessed to identify the efficacy of 3D-AHM as a functional delivery mechanism and to lay a framework for heart model development. An alternative strategy for the generation of 3D heart muscle was explored through magnetic levitation of cardiovascular cells. Magnetic sensitivity was appended to cells through incubation with ferromagnetic nanoparticles. The cells were then levitated and cultured within a magnetic field to form 3D multicellular aggregates. (MCAs) We utilized a magnetized fibrin gel scaffold in order to apply non-contact, magnetic stretch conditioning to our AHM model through a novel bioreactor system.
We were able to develop a highly functional 3D-AHM and extracted 4M cells as the optimal concentration for the generation of our artificial heart muscle. Application of a layer of 3D-AHM to an acellular rat heart proved the 3D-AHM an effective mechanism for delivery of a subset of function to a structure. Magnetic levitation generated hundreds of cell-dense, functional and phenotypically relevant heart muscle analogs. We have developed a completely novel system for the application of mechanical stretch conditioning to artificial heart muscle models and are working to implement more complex conditioning systems. The work presented herein surveys the generation of 3 unique cardiovascular model systems and a novel method for model conditioning.